B-cell receptor (BCR) complex and its associated proteins play a critical role in the development, proliferation and survival of normal or malignant B cells. BCR function is required for normal antibody production and abnormal BCR signal transduction is implicated in B-cell malignancies. BCR signal transduction operates through several signaling pathways, including the PLCγ/calcium/NFAT pathway, the PI3K pathway, the IKK/NF-κB pathway and the canonical ERK pathway.
Phospholipase C gamma 2 (PLCγ2) is an enzyme of the phospholipase C family that cleaves the phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) into diacyl glycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG remains bound to the membrane, and IP3 is released as a soluble structure into the cytosol. IP3 then diffuses through the cytosol to bind to IP3 receptors, particular calcium channels in the smooth endoplasmic reticulum (ER). This causes the cytosolic concentration of calcium to increase, causing a cascade of intracellular changes and activity. In addition, calcium and DAG together work to activate protein kinase C, which goes on to phosphorylate other molecules within the pathway, leading to altered cellular activity. In some cases, the mutant PLCγ2 polypeptide are constitutively active (i.e. does not require phosphorylation by BTK).